A Study of Three Drugs Plus Zidovudine in the Prevention of Infections in HIV-Infected Patients

• ClinicalTrials.gov Identifier: NCT00000991
• Recruitment Status: Completed
• First Posted: August 31, 2001
• Last Update Posted: March 29, 2012
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

To evaluate and compare 3 anti-pneumocystis regimens plus zidovudine (AZT) in persons with HIV infection and T4 cell count less than 200 cells/mm3. All persons completing at least 8 weeks of therapy on 081 will be offered the opportunity to participate in the nested study (ACTG 981) of systemic antifungal therapy (fluconazole) versus local therapy (Clotrimazole) for the prevention of serious fungal disease.

Persons with HIV disease who are receiving AZT are at risk for PCP, toxoplasmosis, bacterial pneumonia, and other serious infections. It is therefore important to find drugs that can be given along with AZT to control these infections. Aerosolized pentamidine (PEN) has been shown to be useful in preventing PCP and is expected to lower the 2-year risk of PCP. Both sulfamethoxazole/trimethoprim (SMX/TMP) and dapsone probably also provide effective preventive treatment against PCP, and both may be useful in preventing toxoplasmosis and extrapulmonary pneumocystosis.

Condition or disease	Intervention/treatment	Phase
Pneumonia, Pneumocystis Carinii; HIV Infections	Drug: Pentamidine isethionate; Drug: Sulfamethoxazole-Trimethoprim; Drug: Dapsone; Drug: Zidovudine	Phase 3

Detailed Description:

Persons with HIV disease who are receiving AZT are at risk for PCP, toxoplasmosis, bacterial pneumonia, and other serious infections. It is therefore important to find drugs that can be given along with AZT to control these infections. Aerosolized pentamidine (PEN) has been shown to be useful in preventing PCP and is expected to lower the 2-year risk of PCP. Both sulfamethoxazole/trimethoprim (SMX/TMP) and dapsone probably also provide effective preventive treatment against PCP, and both may be useful in preventing toxoplasmosis and extrapulmonary pneumocystosis.

All patients receive AZT. In addition, they are placed in one of three groups to receive either SMX/TMP, dapsone, or PEN. Stratification criteria are:

Received first AZT equal to or less than 6 weeks prior to study entry. Received first AZT more than 6 weeks prior to study entry. Potential to participate in ACTG 981. ACTG center in which the patient is enrolled.

Study Design

• Study Type: Interventional (Clinical Trial)
• Enrollment: 600 participants
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial of Three Anti-Pneumocystis Agents Plus Zidovudine for the Primary Prevention of Serious Infections in Patients With Advanced HIV Infection
• Actual Study Completion Date: April 1994

Arms and Interventions

Outcome Measures

Eligibility Criteria

• Ages Eligible for Study: 13 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

• Antifolate medication required to treat an intercurrent infection.
• Treatment of intercurrent infections or malignancies.
• Fluconazole.
• Itraconazole.
• Standard or investigational therapy for pneumocystosis (PCP) or toxoplasmosis.
• Only the forms of primary prophylaxis for PCP or toxoplasmosis assigned to the participant under the protocol. Patients who develop intolerance to all forms of prophylaxis assigned in this protocol or who develop PCP or toxoplasmosis may receive alternate or investigation forms of prophylaxis with or without zidovudine but must continue to be followed under this protocol.
• Discouraged but allowed: AL-721.
• Chronic acyclovir.
• Ketoconazole.
• Amphotericin B.
• Corticosteroids at greater than physiologic replacement doses are strongly discouraged.
• They should be used as briefly as possible and only for definite specific indications.

Patient must conform to the following:

• Receiving or candidates for zidovudine therapy at least 500 mg/day under current labeled indications with no history of pneumocystosis (PCP) or toxoplasmosis.
• Evidence of HIV infection documented by HIV antibody tests.
• T4 cell count less than 200 cells/mm3 at any time prior to study entry.
• Willing to sign informed consent.
• Willing to be followed by a participating ACTG center for duration of the study.
• Allowed: Concurrent enrollment in long-term follow-up studies in previously blinded trials of AZT (ACTG 016 and 019).

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions are excluded:

• History of documented or presumed pneumocystosis (PCP) or toxoplasmosis.
• Active bacterial or mycobacterial infection.
• History of type I hypersensitivity, exfoliative rash, or rash with mucosal involvement, severe bronchospasm, or other life-threatening reaction to any of the study drugs or to other sulfas, sulfones, or pentamidine.
• History of intolerance causing dose interruption while receiving zidovudine at equal to or less than 600 mg/day or causing dose reduction to less than 500 mg/day within 4 weeks prior to entry.
• Advanced Kaposi's sarcoma or other malignancy not specifically allowed that has been rapidly progressive during the month prior to enrollment or which may be expected to require chemotherapy within 90 days of study entry.

Concurrent Medication:

Excluded:

• Active primary treatment for an infection or malignancy.
• Other form of antifolate medication not specifically allowed.
• Other antiretroviral or biologic response modifier.
• Ganciclovir, if it causes intolerance to AZT equal to or more than 500 mg/day.
• Foscarnet.

Patients with the following are excluded:

• Symptoms and conditions defined in Exclusion Coexisting Conditions.
• Glucose 6-phosphate dehydrogenase deficiency (GPD).
• History of pneumocystosis (PCP) or toxoplasmosis.
• History of type I hypersensitivity, exfoliative rash, or rash with mucosal involvement, severe bronchospasm, or other life-threatening reaction to any of the study drugs or to other sulfas, sulfones, or pentamidine.
• History of intolerance causing dose interruption while receiving zidovudine at equal to or less than 500 mg/day with 4 weeks pior to study entry.

Prior Medication:

Excluded within 4 weeks of study entry:

• Any other form of pneumocystosis (PCP) chemoprophylaxis.
• Active substance abuse, including alcohol.

Contacts and Locations

Locations

United States, California

USC CRS

Los Angeles, California, United States, 90033

Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.

Oakland, California, United States, 94609

Ucsd, Avrc Crs

San Diego, California, United States, 92103

United States, Florida

Univ. of Miami AIDS CRS

Miami, Florida, United States, 33136

United States, Illinois

Chicago Children's CRS

Chicago, Illinois, United States, 60614

United States, Indiana

Indiana Univ. School of Medicine, Infectious Disease Research Clinic

Indianapolis, Indiana, United States, 46202

United States, Maryland

Johns Hopkins Adult AIDS CRS

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Massachusetts General Hospital ACTG CRS

Boston, Massachusetts, United States, 02114

Beth Israel Deaconess - East Campus A0102 CRS

Boston, Massachusetts, United States, 02215

Beth Israel Deaconess Med. Ctr., ACTG CRS

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota, ACTU

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Washington U CRS

St. Louis, Missouri, United States

United States, New York

SUNY - Buffalo, Erie County Medical Ctr.

Buffalo, New York, United States, 14215

Univ. of Rochester ACTG CRS

Rochester, New York, United States

United States, North Carolina

Unc Aids Crs

Chapel Hill, North Carolina, United States

Duke Univ. Med. Ctr. Adult CRS

Durham, North Carolina, United States

United States, Ohio

Case CRS

Cleveland, Ohio, United States, 44106

The Ohio State Univ. AIDS CRS

Columbus, Ohio, United States, 43210

United States, Pennsylvania

Pitt CRS

Pittsburgh, Pennsylvania, United States

United States, Washington

University of Washington AIDS CRS

Seattle, Washington, United States, 98105

Tanzania

Mbeya Med. Research Program, Mbeya Referral Hosp. CRS

Mbeya, Tanzania

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: S Bozzette
• Study Chair: S Spector

More Information

Publications:

Bozzette SA, Hays RD, Berry SH, Kanouse DE. A Perceived Health Index for use in persons with advanced HIV disease: derivation, reliability, and validity. Med Care. 1994 Jul;32(7):716-31.

Bozzette SA, Finkelstein DM, Spector SA, Frame P, Powderly WG, He W, Phillips L, Craven D, van der Horst C, Feinberg J. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995 Mar 16;332(11):693-9.

Glick ME. CTG studies yield results. AIDS Clinical Trials Group. NIAID AIDS Agenda. 1995 Spring:8-9.

Justice AC, Rabeneck L, Hays RD, Wu AW, Bozzette SA. Sensitivity, specificity, reliability, and clinical validity of provider-reported symptoms: a comparison with self-reported symptoms. Outcomes Committee of the AIDS Clinical Trials Group. J Acquir Immune Defic Syndr. 1999 Jun 1;21(2):126-33.

Justice AC, Holmes W, Gifford AL, Rabeneck L, Zackin R, Sinclair G, Weissman S, Neidig J, Marcus C, Chesney M, Cohn SE, Wu AW; Adult AIDS Clinical Trials Unit Outcomes Committee. Development and validation of a self-completed HIV symptom index. J Clin Epidemiol. 2001 Dec;54 Suppl 1:S77-90.

Ioannidis JP, Dixon DO, McIntosh M, Albert JM, Bozzette SA, Schnittman SM. Relationship between event rates and treatment effects in clinical site differences within multicenter trials: an example from primary Pneumocystis carinii prophylaxis. Control Clin Trials. 1999 Jun;20(3):253-66.

DiRienzo AG, van Der Horst C, Finkelstein DM, Frame P, Bozzette SA, Tashima KT. Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection. AIDS Res Hum Retroviruses. 2002 Jan 20;18(2):89-94.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00000991 History of Changes
• Other Study ID Numbers: ACTG 081; 11056 ( Registry Identifier: DAIDS ES Registry Number )
• First Posted: August 31, 2001
• Last Update Posted: March 29, 2012
• Last Verified: March 2012

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Trimethoprim-Sulfamethoxazole Combination; Toxoplasmosis; AIDS-Related Opportunistic Infections; Pneumonia, Pneumocystis carinii; Pentamidine; Dapsone; Drug Evaluation; Drug Therapy, Combination; Acquired Immunodeficiency Syndrome; Zidovudine; Sulfamethoxazole-Trimethoprim

Additional relevant MeSH terms:

Infection; Communicable Diseases; Pneumonia, Pneumocystis; HIV Infections; Acquired Immunodeficiency Syndrome; Pneumonia; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Lung Diseases, Fungal; Mycoses; Pneumocystis Infections; Zidovudine; Trimethoprim; Sulfamethoxazole; Dapsone; Pentamidine; Trimethoprim, Sulfamethoxazole Drug Combination; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Reverse Transcriptase Inhibitors